DESCRIPTION (Applicant's Description): The goal of this research is to clarify the pathogenesis of diabetic retinopathy and to provide a rational basis for developing improved means to inhibit the retinopathy. The proposed studies are based on our recent findings that aminoguanidine and aspirin both inhibit the development of retinopathy in diabetes. We will investigate the hypothesis that aminoguanidine and aspirin inhibit retinal pathology by inhibiting the same metabolic abnormalities in diabetes, especially excessive production of NO and of reactive dicarbonyls. The pathogenesis of diabetic retinopathy will be investigated by comparing effects of aminoguanidine and aspirin on retinal metabolism and histopathology to results observed using selective inhibitors of (1) dicarbonyl (and advanced glycation end product) production, (2) nitric oxide synthesis, and (3) poly (ADP-ribose) synthetase. Together, these selective inhibitors will investigate the roles of hyperglycemia-induced damage to DNA, caspase activation, and accelerated death of retinal capillary cells in the pathogenesis of diabetic retinopathy. Additional insight on how aminoguanidine inhibits retinopathy in diabetes will be gained by investigating why aminoguanidine fails to inhibit the morphologically similar retinopathy caused by galactose-feeding.